MT1-MMP-Deficient Mice Develop Dwarfism, Osteopenia, Arthritis, and Connective Tissue Disease due to Inadequate Collagen Turnover

Holmbeck, Kenn; Bianco, Paolo; Caterina, John J.; Yamada, Susan S.; Kromer, Mark; Kuznetsov, Sergei A.; Mankani, Mahesh H.; Robey, Pamela Gehron; Poole, A. Robin; Pidoux, I; Ward, Jerrold M.; Birkedal‐Hansen, Henning

doi:10.1016/s0092-8674(00)80064-1

Cited by 1,197 publications

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“…Mmp14 knockouts are the only lethal MMPmutant mice; the mice are normal at birth but develop multiple abnormalities and die by 3-12 weeks 42,43 . Mmp14 mutants are grossly defective in the remodelling of the connective tissue.…”

Section: Mmp14 Deficiency Results In Lethalitymentioning

confidence: 99%

“…Mmp14 mutants are grossly defective in the remodelling of the connective tissue. Loss of an ECM-degrading enzyme would be expected to result in increased bone deposition; paradoxically, Mmp14 mutants instead show secondary effects of increased bone resorption and defective secondary ossification centres 42,43 . Osteogenic cells from Mmp14-mutant mice cannot degrade collagen and do not form bone when transplanted subcutaneously into host immunodeficient mice 42 .…”

Section: Mmp14 Deficiency Results In Lethalitymentioning

confidence: 99%

“…Loss of an ECM-degrading enzyme would be expected to result in increased bone deposition; paradoxically, Mmp14 mutants instead show secondary effects of increased bone resorption and defective secondary ossification centres 42,43 . Osteogenic cells from Mmp14-mutant mice cannot degrade collagen and do not form bone when transplanted subcutaneously into host immunodeficient mice 42 . Taken together, the phenotypes of Mmp14-mutant mice strongly support the physiological relevance of the in vitro data, which show that collagen types I, II and III are substrates for MMP14 (REF.…”

Section: Mmp14 Deficiency Results In Lethalitymentioning

confidence: 99%

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Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

2,560

2,180

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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Section: Mmp14 Deficiency Results In Lethalitymentioning

confidence: 99%

Section: Mmp14 Deficiency Results In Lethalitymentioning

confidence: 99%

Section: Mmp14 Deficiency Results In Lethalitymentioning

confidence: 99%

See 1 more Smart Citation

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

2,560

2,180

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“…29 MT1-MMP null mice develop dwarfism and die within months of birth because of a failure to remodel type I collagen. 38,39 These observations have drawn attention to the possible key role of MT1-MMP in matrix turnover.…”

Section: Matrix Metalloproteases In Cancermentioning

confidence: 99%

Matrix metalloproteases in head and neck cancer

Rosenthal¹,

2006

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Matrix metalloproteases (MMPs) are a collection of enzymes capable of cleaving extracellular matrix components, growth factors, and cell-surface receptors. MMPs modulate most aspects of tumorigenesis and are highly expressed in cancer compared with normal tissues. Preclinical studies have demonstrated that head and neck squamous cell carcinomas (HNSCCs) express high levels of MMPs in vivo and that inhibition of these enzymes in vitro and in mouse models decreases invasion and metastasis. However, the clinical trials for MMP inhibitors have failed to demonstrate a significant survival advantage in most cancers. The disparity between preclinical and clinical studies has led to the reevaluation of how MMP functions in cancer and the design of clinical trials for molecularly targeted agents. Mouse model data and analysis of HNSCC tumor specimens suggests that membrane type-1 MMP (MT1-MMP) may be a critical enzyme in tumor cell invasion and survival in vivo. This accumulated data provide evidence for development of selective MT1-MMP inhibitors as therapy in HNSCC.Keywords matrix metalloprotease inhibitor; MMP; extracellular matrix; head and neck cancer; squamous cell carcinoma; membrane type-1 MMP; drug development; proteases The hallmark of cancer remains regional and distant metastases. Regional metastasis in head and neck squamous cell carcinoma (HNSCC) decreases survival by almost 50%, and invasion beyond the lymph node capsule further decreases survival. 1 For tumor cells to invade and metastasize they must: (1) develop motility, (2) alter cell-cell and cell-matrix adhesion, and (3) remodel the extracellular matrix. 2 It was recognized in the 1980s that matrix metalloprotease (MMP) could degrade extracellular matrix (ECM) components and that this could potentiate local tumor invasion and metastasis. 3 A significant amount of effort has been funneled into the development of MMP inhibitors (MPIs) promote tumor angiogenesis by mobilizing or activating factors such as basic fibroblast growth factor, vascular endothelial growth factor, or transforming growth factor-beta. 15,16,18 Second, the complexity of cell types expressing MMPs in the tumor mass was appreciated ( Figure 1 ASSESSMENT OF MATRIX METALLOPROTEASES IN HEAD AND NECK CANCERMMPs consistently found overexpressed in head and neck cancer include MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, and MMP-14 (Table 1). However, MMP-1, MMP-2, MMP-9, and MT-1 MMP are most commonly identified in HNSCC and associated with disease progression. With the understanding that conflicting reports are abundant and negative studies unlikely to be published, it is possible to summarize the extensive MMP findings in HNSCC. Although most studies evaluate only one or two MMPs within a given head and neck site, studies have examined expression of multiple TIMPs and MMPs in oral cavity SCC. 12,22 Interestingly, these studies commonly identify upregulation of TIMP-1, which is associated with a poor survival. Levels of TIMP-2 are often unchanged between t...

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“…Metastasis growth is thought to be dependent on expression of genes involved in angiogenesis, but additional genes are likely to be required. Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases which have a role in degradation of the extracellular matrix components, 16,17 as well as angiogenesis [18][19][20][21] and have been involved in facilitating tumor cell invasion and metastasis. These proteins share a common domain with a family of proteins which play an opposite role, the tissue inhibitors of metalloproteinases (TIMPs), which inhibit MMPs by forming tight-binding, non-covalent association with the active site of MMPs.…”

mentioning

confidence: 99%

Systemic gene therapy with anti-angiogenic factors inhibits spontaneous breast tumor growth and metastasis in MMTVneu transgenic mice

Sacco¹,

Catò²,

Ceruti

et al. 2001

Gene Ther

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Tumor growth and metastasis are angiogenesis-dependent. The possibility of inhibiting tumor growth by interfering with the formation of new vessels has recently raised considerable interest. We previously reported that it is possible to inhibit primary tumor growth and metastasis in a transgenic model of spontaneous breast tumor, which shows many similarities to its human counterpart (including ability to metastasize) by intratumoral administration of a DNA conKeywords: gene therapy; breast adenocarcinoma; metastasis; transgenic mice; anti-angiogenesis; liposomesIt is now widely recognized that the development of new blood vessels (angiogenesis) is necessary to sustain tumor growth, invasion and metastasis. At some point during tumor growth, cancer cells acquire the ability to activate the quiescent vasculature to produce new blood vessels via a so-called 'angiogenic switch '. 1,2 Although the need for recruiting new blood vessels to the tumor has been know for more than two decades, the possibility of treating malignancies by acting on their vasculature has become popular only since the isolation of endogenous angiogenesis inhibitors, which dramatically affect cancer growth in experimental murine systems. Highly promising results on experimental tumors in rodents using these inhibitors as purified proteins as well as transduced genes, alone or in combination with traditional therapies have been reported. [3][4][5][6][7] The establishment of a dormancy status, which in some cases persists even after the suspension of therapy, has been obtained with these gene products, 5 and this, together with the absence of drug resistance, 8 raised the possibility that the anti-angiogenic effects could be useful in the treatment of human tumors.The achievement of the inhibition of local tumor growth is the usual end-point of these therapeutical attempts, but in humans it is the metastatic spread that is responsible for the majority of cancer-related deaths. Therefore, to be really useful in the human context, any new approach must be evaluated in its ability to interfere Correspondence: MG Sacco, ITBA CNR, Via F lli Cervi, 93, 20090 Segrate (MI), Italy Received 17 August 2000; accepted 11 October 2000 struct carrying the murine angiostatin cDNA driven by liposomes. Here we report that it is also possible to achieve this goal by a systemic (intraperitoneal) delivery of therapeutic DNA constructs carrying genes coding for mouse and human anti-angiogenic factors which include angiostatin, endostatin and TIMP-2. These findings may be relevant to the design of therapeutic interventions in humans. Gene Therapy (2001) 8, 67-70. with tumor cell invasion and metastasis, a therapeutical target which is rarely, if ever, investigated at the experimental level. Unfortunately, most of the results in experimental oncology have been obtained on transplantable tumors which are usually generated by inoculating highly malignant cultured cells, which rapidly grow in the site of injection and become the target for therapeutic intervention. ...

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MT1-MMP-Deficient Mice Develop Dwarfism, Osteopenia, Arthritis, and Connective Tissue Disease due to Inadequate Collagen Turnover

Cited by 1,197 publications

References 43 publications

Matrix metalloproteinases and the regulation of tissue remodelling

Matrix metalloproteinases and the regulation of tissue remodelling

Matrix metalloproteases in head and neck cancer

Systemic gene therapy with anti-angiogenic factors inhibits spontaneous breast tumor growth and metastasis in MMTVneu transgenic mice

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